PROJECT SUMMARY/ABSTRACT Asthma prevalence in Puerto Ricans is 37% versus 12% for whites yet most studies have been conducted among the latter. This asthma burden extends to asthma morbidity and mortality, which are 2.4- and 4-fold higher among Puerto Ricans compared to whites, respectively. There is a strong association between severe, early-life viral respiratory illnesses and development of childhood recurrent wheeze and asthma. However, little is known about the mechanisms underlying these associations. Does airway dysfunction exist at birth and first manifest in early life as a severe illness in response to viral respiratory infections, and later as childhood asthma? Or does a severe, early-life respiratory illness injure a normal airway and precipitate asthma later in childhood? We will study Puerto Rican children to address these questions via three Specific Aims. Aim 1: Recruit a cohort of 3,000 newborns to longitudinally study the effects of early-life viral respiratory illnesses on nasal airway molecular endotype and risk for recurrent wheeze. We will collect yearly environmental, social, and clinical data on each participant and track all respiratory illnesses from birth to age 3. We will record severity and presence of wheezing in each child's illnesses and collect nasal swabs to determine the presence/type of virus associated with these illnesses. Aim 2: Identify viral and genetic determinants of severe early-life respiratory illnesses and whether the molecular state of the nasal airway epithelium at birth is predictive of these severe illnesses. We will perform transcriptomic and viral analyses on nasal airway swabs from subjects at birth and during respiratory illness. We will test if severe respiratory illnesses are associated with viral infection in general and/or infection with a specific viral species. We will use genome-wide genetic data to identify risk variants for severe early-life respiratory illnesses and variants influencing airway gene expression at birth and during illness (eQTLs). We will test for GxE interactions between top risk variants/eQTLs and infection with different viral species. We will also identify gene expression response to mild vs. severe early-life respiratory illnesses and determine if airway gene expression at birth is predictive of severe respiratory illness in early childhood. Aim 3: Determine the relationship between severity of early-life respiratory illness and post-illness but pre-asthma nasal airway gene expression profiles. We will perform transcriptomic and viral metagenomic analysis of nasal swabs collected from subjects at age 3. We will determine how severe respiratory illnesses affect the trajectory of airway gene expression profiles from birth to early childhood. Finally, we will determine if mild or severe respiratory illness in early life is predictive of recurrent wheeze at age 3. Our longitudinal birth cohort will [1] be the largest prospective study of minority infants, [2] provide novel and seminal information on genetic/viral risk factors for severe respiratory illnesses, and [3] identify airway endotypes that high-risk groups exhibit at birth and after respiratory illness, but prior to asthma onset. Our study will help to elucidate the relationship between early-life respiratory illness and asthma.